Clinical Trial

. 2024 Jul 8;14(1):107.

doi: 10.1038/s41408-024-01088-6.

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN

Ajai Chari¹, Jonathan L Kaufman², Jacob Laubach³, Douglas W Sborov⁴, Brandi Reeves⁵, Cesar Rodriguez⁶, Rebecca Silbermann⁷, Luciano J Costa⁸, Larry D Anderson Jr⁹, Nitya Nathwani¹⁰, Nina Shah¹¹, Naresh Bumma¹², Sarah A Holstein¹³, Caitlin Costello¹⁴, Andrzej Jakubowiak¹⁵, Tanya M Wildes¹³, Robert Z Orlowski¹⁶, Kenneth H Shain¹⁷, Andrew J Cowan¹⁸, Huiling Pei¹⁹, Annelore Cortoos²⁰, Sharmila Patel²⁰, Thomas S Lin²⁰, Peter M Voorhees²¹, Saad Z Usmani²², Paul G Richardson³

Affiliations

¹ Icahn School of Medicine at Mount Sinai, New York, NY, USA. ajai.chari@ucsf.edu.
² Winship Cancer Institute, Emory University, Atlanta, GA, USA.
³ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁴ Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁵ University of North Carolina-Department of Medicine-Chapel Hill, Chapel Hill, NC, USA.
⁶ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁸ University of Alabama at Birmingham, Birmingham, AL, USA.
⁹ Myeloma, Waldenstrӧm's and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁰ Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹¹ University of California San Francisco, San Francisco, CA, USA.
¹² Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
¹³ Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁴ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁵ University of Chicago Medical Center, Chicago, IL, USA.
¹⁶ Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁷ Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
¹⁸ Clinical Research Division, Fred Hutch Cancer Center, Seattle, WA, USA.
¹⁹ Janssen Research & Development, LLC, Titusville, NJ, USA.
²⁰ Janssen Scientific Affairs, LLC, Horsham, PA, USA.
²¹ Levine Cancer Institute, Atrium Health Wake Forest University School of Medicine, Charlotte, NC, USA. Peter.Voorhees@atriumhealth.org.
²² Memorial Sloan Kettering Cancer Center, New York, NY, USA. usmanis@mskcc.org.

PMID: 38977707
PMCID: PMC11231363
DOI: 10.1038/s41408-024-01088-6

Clinical Trial

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN

Ajai Chari et al. Blood Cancer J. 2024.

. 2024 Jul 8;14(1):107.

doi: 10.1038/s41408-024-01088-6.

Authors

Affiliations

¹ Icahn School of Medicine at Mount Sinai, New York, NY, USA. ajai.chari@ucsf.edu.
² Winship Cancer Institute, Emory University, Atlanta, GA, USA.
³ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁴ Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁵ University of North Carolina-Department of Medicine-Chapel Hill, Chapel Hill, NC, USA.
⁶ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁸ University of Alabama at Birmingham, Birmingham, AL, USA.
⁹ Myeloma, Waldenstrӧm's and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁰ Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹¹ University of California San Francisco, San Francisco, CA, USA.
¹² Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
¹³ Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁴ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁵ University of Chicago Medical Center, Chicago, IL, USA.
¹⁶ Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁷ Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
¹⁸ Clinical Research Division, Fred Hutch Cancer Center, Seattle, WA, USA.
¹⁹ Janssen Research & Development, LLC, Titusville, NJ, USA.
²⁰ Janssen Scientific Affairs, LLC, Horsham, PA, USA.
²¹ Levine Cancer Institute, Atrium Health Wake Forest University School of Medicine, Charlotte, NC, USA. Peter.Voorhees@atriumhealth.org.
²² Memorial Sloan Kettering Cancer Center, New York, NY, USA. usmanis@mskcc.org.

PMID: 38977707
PMCID: PMC11231363
DOI: 10.1038/s41408-024-01088-6

Abstract

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10^-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.

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Conflict of interest statement

JLK served as a consultant for AbbVie, BMS, Heidelberg Pharma, Incyte, Janssen, Novartis, Roche/Genentech, Sanofi, Sutro, and Takeda; received honoraria from AbbVie, Janssen, Roche/Genentech, and Tecnopharma; and holds a membership on a board or advisory committee for Incyte and TG Therapeutics. JL received honoraria from Great Debates & Updates – Hematologic Malignancies. DWS served as a consultant for and holds membership on an entity’s board of directors or advisory committees for Janssen, Arcellx, AbbVie, Pfizer, Sanofi, and Bioline; and served as a consultant for Pfizer, GSK, and Sanofi. BR received honoraria from Incyte, BMS, and PharmaEssentia. CR served as a consultant for Janssen, BMS, Takeda, AbbVie, Karyopharm, and Artiva; and served on a speakers bureau for Janssen, BMS, Takeda, AbbVie, Karyopharm, and Artiva. RS served as a consultant or in an advisory role for Sanofi-Aventis, Janssen Oncology, and Oncopeptides; and received research funding from Sanofi. LJC served as a consultant or in an advisory role for AbbVie, Amgen, Celgene, Karyopharm, and Sanofi; served on a speakers bureau for Amgen and Sanofi; received honoraria from Amgen, Celgene, Janssen, Karyopharm, and Sanofi; and received research funding from Amgen and Janssen. LDA holds a membership on an entity’s Board of Directors or advisory committees for, served as a consultant for, and received honoraria from GSK, BMS, Celgene, Janssen, Amgen, Oncopeptides, Karyopharm, AbbVie, and BeiGene. NS received research funding from BMS/Celgene, Janssen, bluebird bio, Sutro Biopharma, Teneobio, Poseida, Nektar, and Precision BioSciences; served as a consultant for GSK, Amgen, Indapta Therapeutics, Sanofi, CareDx, Kite, Karyopharm, Oncopeptides, and CSL Behring; and is a current employee and equity holder of AstraZeneca. NB served on a speakers bureau for Amgen, Sanofi, and Genzyme; and served on an advisory board for Sanofi, Genzyme, and Janssen. SAH served as a consultant for BMS/Celgene, Janssen, Takeda, Pfizer, Oncopeptides, GSK, Secura Bio, and Sanofi; and received research funding from Oncopeptides. CC received honoraria from Regeneron, Takeda, BMS, Pfizer, and Janssen; and received research funding from Takeda, BMS, Pfizer, Janssen, Ionis, Harpoon, and Poseida. AJ served as a consultant or in an advisory role for and received honoraria from AbbVie, Amgen, BMS, Celgene, GSK, Gracell, Janssen, Karyopharm, and Sanofi. TMW served as a consultant for Carevive, Seattle Genetics, Janssen, and Sanofi. RZO received research funding from Asylia Therapeutics, BioTheryX, Heidelberg Pharma, CARsgen Therapeutics, BMS/Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, and Takeda Pharmaceuticals North America; received honoraria from and holds a membership on an entity’s board of directors or advisory committees for AbbVie, BiotheryX, Inc., BMS, Janssen Biotech, Karyopharm, Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Sanofi-Aventis, and Takeda Pharmaceuticals North America; and is a current stockholder of Asylia Therapeutics. KHS received honoraria from BMS, Janssen, GSK, Adaptive Biotechnologies, Sanofi, Takeda, and Amgen; served as an ad hoc member of advisory committees for GSK, Janssen, and BMS; served on a speakers bureau for GSK, BMS, Sanofi, Karyopharm, Takeda, Janssen, Adaptive Biotechnologies, and Amgen; received research funding from AbbVie and Karyopharm; and is the principal investigator of clinical trials sponsored by Janssen and BMS, with all research outside the scope of the submitted work. AJC served as a consultant for and received research funding from Janssen, BMS, and AbbVie; received research funding from Harpoon, Sanofi-Aventis, and Nektar; served as a consultant for Allogene, EUSA, GSK, and Secura Bio; and received research funding from and holds a membership on an entity’s board of directors or advisory committees for Adaptive Biotechnologies. HP, A Cortoos, SP, and TSL are current equity holders and employees of Janssen. PMV served as a consultant for, received honoraria from, and holds a membership on an entity’s board of directors or advisory committees for AbbVie, Amgen, BMS, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Sanofi, and Secura Bio. SZU served as a consultant for Celgene, Amgen, Janssen Oncology, Seattle Genetics, Takeda, GSK, Karyopharm, AbbVie, SkylineDx, Merck, Oncopeptides, Genentech, Gilead Sciences, and BMS/Celgene; served on a speakers bureau for Takeda, Amgen, Janssen Oncology, Sanofi, and BMS/Celgene; and received research funding from Celgene and Array BioPharma. PGR received research funding from Oncopeptides, BMS/Celgene, Takeda, and Karyopharm; and served on advisory committees for Oncopeptides, BMS/Celgene, Takeda, Karyopharm, Janssen, Sanofi, Secura Bio, GSK, Regeneron, AstraZeneca, and Protocol Intelligence. A Chari and NN have nothing to disclose.

Figures

**Fig. 1. Subgroup analysis of MRD-negativity (10⁻⁵) rates by the end of the study.**
MRD-negativity rates for all groups were evaluated at the time of the final analysis (median overall follow-up, 49.6 months). MRD was evaluated by next-generation sequencing using the clonoSEQ assay (v2.0; Adaptive Biotechnologies, Seattle, WA) at a minimum sensitivity threshold of 1 in 100,000 cells (10⁻⁵) in alignment with IMWG criteria [44]. MRD minimal residual disease, D-RVd daratumumab plus lenalidomide/bortezomib/dexamethasone, RVd lenalidomide/bortezomib/dexamethasone, CI confidence interval, ITT intent-to-treat, ISS International Staging System, HRCA high-risk cytogenetic abnormality, NE not evaluable, VGPR very good partial response, FISH fluorescence in situ hybridization. ^aMantel–Haenszel estimate of the common odds ratio for unstratified tables is used. An odds ratio > 1 indicates an advantage for D-RVd. ^bHigh-risk cytogenetics are defined based on FISH testing as ≥ 1 of the following: del(17p), t(4;14), or t(14;16). ^cRevised high-risk cytogenetics are defined based on FISH testing as ≥ 1 HRCA: del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥ 3 copies of chromosome 1q21). ^dPatients in this group have gain/amp(1q21) with or without other HRCAs (del[17p], t[4;14], t[14;16], or t[14;20]). ^ePatients with isolated gain/amp(1q21) do not have any other HRCAs.

**Fig. 2. Subgroup analysis of MRD-negativity (10⁻⁵) rates among patients with a best response of ≥ CR by the end of the study.**
MRD-negativity rates were evaluated among response-evaluable patients^a who achieved a best response of ≥ CR and were measured at the time of the final analysis (median follow-up in overall population, 49.6 months). MRD was evaluated by next-generation sequencing using the clonoSEQ assay (v2.0; Adaptive Biotechnologies, Seattle, WA) at a minimum sensitivity threshold of 1 in 100,000 cells (10⁻⁵) in alignment with IMWG criteria [44]. MRD minimal residual disease, D-RVd daratumumab plus lenalidomide/bortezomib/dexamethasone, RVd lenalidomide/bortezomib/dexamethasone, CI confidence interval, ITT intent-to-treat, ISS International Staging System, HRCA high-risk cytogenetic abnormality, NE not evaluable, VGPR very good partial response, FISH fluorescence in situ hybridization. ^aMantel–Haenszel estimate of the common odds ratio for unstratified tables is used. An odds ratio > 1 indicates an advantage for D-RVd. ^bThis analysis included patients from the response-evaluable population, which included all randomized patients who had measurable disease (confirmed MM diagnosis), received ≥ 1 dose of study treatment, and had ≥ 1 postbaseline disease assessment. ^cHigh-risk cytogenetics are defined based on FISH testing as ≥ 1 of the following: del(17p), t(4;14), or t(14;16). ^dRevised high-risk cytogenetics are defined based on FISH testing as ≥ 1 HRCA: del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥ 3 copies of chromosome 1q21). ^ePatients in this group have gain/amp(1q21) with or without other HRCAs (del[17p], t[4;14], t[14;16], or t[14;20]). ^fPatients with isolated gain/amp(1q21) do not have any other HRCAs.

**Fig. 3. Subgroup analysis of rates of sustained MRD negativity (10⁻⁵) lasting ≥ 12 months.**
MRD-negativity rates for all groups were evaluated at the time of the final analysis (median overall follow-up, 49.6 months). MRD was evaluated by next-generation sequencing using the clonoSEQ assay (v2.0; Adaptive Biotechnologies, Seattle, WA) at a minimum sensitivity threshold of 1 in 100,000 cells (10⁻⁵) in alignment with IMWG criteria [44]. MRD minimal residual disease, D-RVd daratumumab plus lenalidomide/bortezomib/dexamethasone, RVd lenalidomide/bortezomib/dexamethasone, CI confidence interval, ITT intent-to-treat, ISS International Staging System, HRCA high-risk cytogenetic abnormality, NE not evaluable, VGPR very good partial response, FISH fluorescence in situ hybridization. ^aMantel–Haenszel estimate of the common odds ratio for unstratified tables is used. An odds ratio > 1 indicates an advantage for D-RVd. ^bHigh-risk cytogenetics are defined based on FISH testing as ≥ 1 of the following: del(17p), t(4;14), or t(14;16). ^cRevised high-risk cytogenetics are defined based on FISH testing as ≥ 1 HRCA: del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥ 3 copies of chromosome 1q21). ^dPatients in this group have gain/amp(1q21) with or without other HRCAs (del[17p], t[4;14], t[14;16], or t[14;20]). ^ePatients with isolated gain/amp(1q21) do not have any other HRCAs.

**Fig. 4. Subgroup analysis of PFS.**
Results of the PFS HR point estimates and their 95% CIs among clinically relevant subgroups of patients. PFS analyses for all groups were evaluated at the time of the final analysis (median overall follow-up, 49.6 months). PFS progression-free survival, D-RVd daratumumab plus lenalidomide/bortezomib/dexamethasone, RVd lenalidomide/bortezomib/dexamethasone, CI confidence interval, ITT intent-to-treat, NR not reached, ISS International Staging System, NE not evaluable, HRCA high-risk cytogenetic abnormality, VGPR very good partial response, MRD minimal residual disease, FISH fluorescence in situ hybridization, HR hazard ratio. ^aHR and 95% CI are from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR < 1 indicates an advantage for D-RVd. ^bHigh-risk cytogenetics are defined based on FISH testing as ≥ 1 of the following: del(17p), t(4;14), or t(14;16). ^cRevised high-risk cytogenetics are defined based on FISH testing as ≥ 1 HRCA: del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥ 3 copies of chromosome 1q21). ^dPatients in this group have gain/amp(1q21) with or without other HRCAs (del[17p], t[4;14], t[14;16], or t[14;20]). ^ePatients with isolated gain/amp(1q21) do not have any other HRCAs.

**Fig. 5. Subgroup analysis of PFS.**
PFS is shown A by NDMM disease with 0, 1, or ≥ 2 HRCAs^a, B among patients with gain/amp(1q21)^b, C by VGPR status by the end of induction, and D by MRD status (10⁻⁵) by the end of consolidation. Results of the Kaplan–Meier estimates of PFS among clinically relevant subgroups of patients are shown and were evaluated at the time of the final analysis (median follow-up, 49.6 months). PFS progression-free survival, VGPR very good partial response, MRD minimal residual disease, NDMM newly diagnosed multiple myeloma, HRCA high-risk cytogenetic abnormality, D-RVd daratumumab plus lenalidomide/bortezomib/dexamethasone, RVd lenalidomide/bortezomib/dexamethasone, FISH fluorescence in situ hybridization. ^aHRCA groups are based on FISH testing as the absence (0 HRCA) or presence of ≥ 1 of the following: del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥ 3 copies of chromosome 1q21). ^bPatients in this group have gain/amp(1q21) with or without other HRCAs (del[17p], t[4;14], t[14;16], or t[14;20]).

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References

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Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN

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Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN

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